Research ArticleAnti-angiogenesis

5-Lipoxygenase Metabolite 4-HDHA Is a Mediator of the Antiangiogenic Effect of ω-3 Polyunsaturated Fatty Acids

Science Translational Medicine  09 Feb 2011:
Vol. 3, Issue 69, pp. 69ra12
DOI: 10.1126/scitranslmed.3001571

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LOX and Vessels

In a dreaded morning ritual, parents once force-fed cod liver oil—a source of vitamin D—to their children to prevent rickets. Today, fish oil has a new star: ω-3 polyunsaturated fatty acids (PUFAs). These molecules—eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—can protect against the abnormal growth of blood vessels, a prime contributor to diabetes-related blindness and retinopathy associated with premature birth. Sapieha et al. have now enriched our understanding of the mechanism behind this protection by showing that the production of a DHA metabolite, 4-hydroxy-docosahexaenoic acid (4-HDHA), by the enzyme 5-lipoxygenase (5-LOX) is one of the main metabolic pathways required for the antiangiogenic effect. 4-HDHA acts via peroxisome proliferator–activated receptor γ (PPARγ) to directly inhibit the sprouting and proliferation of endothelial cells—those that line the inner surfaces of blood vessels.

Mice that are exposed to high amounts of oxygen (75%) from day 7 to 12 after birth and then returned to ambient air develop abnormal revascularization of the retina. Using this system as an approximation of human retinal revascularization, the authors found that feeding mice a diet high in ω-3 PUFAs, but not ω-6 PUFAs, could prevent this event. By genetically removing, one by one, each of the four main enzymes that convert these ω-3 PUFAs to active metabolites, the authors found that protection against revascularization required 5-LOX, a non–heme iron dioxygenase that generates leukotrienes, lipoxins, and the recently identified ω-3 PUFA–derived resolvins and protectins. After identifying the critical 5-LOX as the one present in white blood cells, Sapieha et al. found that large amounts of DHA metabolites were generated under stress conditions such as those that produce retinopathy in premature newborns. One metabolite, 4-HDHA, was detected in the serum and white blood cells of mice and humans and in retinas of mice with oxygen-induced retinopathy. 4-HDHA is known to act through the PPARγ receptor, and pharmacological inhibition of PPARγ interfered with the ability of the ω-3 diet to alleviate oxygen-induced retinopathy in the mice. These results elucidate an important pathway through which ω-3 oils protect against retinopathy and perhaps exert some of their other beneficial effects: oxidation of ω-3 PUFAs by 5-LOX and subsequent inhibition of angiogenesis via PPARγ activation. One implication of this work is good news for those who take aspirin and ibuprofen: The cyclooxygenase inhibition by these agents will not interfere with the healthy effects of your daily dose of fish oil.


  • * These authors contributed equally to this work.

  • Present address: Massachusetts Eye and Ear Infirmary, Angiogenesis Laboratory, Department of Ophthalmology, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.

  • Citation: P. Sapieha, A. Stahl, J. Chen, M. R. Seaward, K. L. Willett, N. M. Krah, R. J. Dennison, K. M. Connor, C. M. Aderman, E. Liclican, A. Carughi, D. Perelman, Y. Kanaoka, J. P. SanGiovanni, K. Gronert, L. E. H. Smith, 5-Lipoxygenase Metabolite 4-HDHA Is a Mediator of the Antiangiogenic Effect of ω-3 Polyunsaturated Fatty Acids. Sci. Transl. Med. 3, 69ra12 (2011).

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